mtDNA Segregation in Heteroplasmic Tissues Is Common In Vivo and Modulated by Haplotype Differences and Developmental Stage

mtDNA Segregation in Heteroplasmic Tissues Is Common In Vivo and Modulated by Haplotype Differences and Developmental Stage

http://www.cell.com/cell-reports/abstract/S2211-1247%2814%2900395-7

Different mtDNA haplotypes can coexist inside the same cell, as a result of mutation, or as a consequence of recently-proposed medical therapies. Several studies have shown that haplotypes involving harmful mutations experience segregation -- they are outcompeted in cells over time, perhaps due to mitochondrial quality control. But little evidence exists exploring segregation between two natural and functional haplotypes, except in one model case. In medical applications, such a mixture of natural, functional haplotypes may be expected to arise, as cells will contain haplotype pairs sampled from a diverse population.

This research constructed new model mice, with their cells containing (a) mtDNA from mice captured from wild populations in Europe paired with (b) mtDNA from lab mice. This wild mtDNA was sequenced, and four different samples were chosen (a1), (a2), (a3), (a4), so that the genetic differences in the pairs (a1)-(b) ... (a4)-(b) represented the expected differences in samples from a human population. Measurements of the proportion of (a) in many different cell types was measured, and new mathematical modelling and statistics were used to powerfully compare results from across many different mice.

Segregation, surprisingly, was very common, across a wide range of tissues, including post-mitotic tissues like heart and muscle, of particular relevance for mitochondrial disease. It was often observed that (a) came to dominate over (b) (though sometimes (b) won), and the rms speed at which this domination occurred was proportional to the genetic distance between (a) and (b). Furthermore, new dynamic regimes of segregation were found, including a constant rate of proliferation of one haplotype over another, a constant proliferation during early development then stabilisation, and a constant proliferation during much of life then stabilisation in old age.